Inhibition of Programmed Death Receptor-1/Programmed Death Ligand-1 Interactions by Ginsenoside Metabolites.

Nam-Hui Yim,Young Soo Kim,Hwan-Suck Chung

doi:10.3390/molecules25092068

Nam-Hui Yim, Young Soo Kim + Show 1 more

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https://doi.org/10.3390/molecules25092068

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Abstract

Evidence suggests that programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) targeted inhibitors act as an immune checkpoint blockade, indicating that these compounds may be useful in cancer immunotherapy by inhibiting the immune response between T-cells and tumors. Previous studies have shown that ginsenosides can regulate the expression of PD-1 and PD-L1 in target diseases; however, it remains unknown whether ginsenosides act as a blockade of PD-1/PD-L1 interactions. In this study, we used competitive ELISA to investigate 12 ginsenosides for their ability to block PD-1/PD-L1 interactions. In addition, we performed a protein–ligand docking simulation and examined the hydrophobic interactions and hydrogen bonds formed at the interfaces between the ginsenosides and PD-L1/PD-1. Eight out of the 12 ginsenosides studied showed inhibition of PD-1/PD-L1 interactions at 35% at the maximum concentration (1 μM). Among them, Rg3 and Compound K (C-K) demonstrated the highest inhibitory effects. Rg3 and C-K were further identified for their interaction efficacy with PD-1/PD-L1, which supported our results demonstrating the blocking activity of these compounds against PD-1/PD-L1 binding interactions. Collectively, our findings suggest that some ginsenosides, including Rg3 and C-K, inhibit PD-1/PD-L1 binding interactions. Therefore, these compounds may prove useful as part of an overall immuno-oncological strategy.

Highlights

Studies of potential anticancer compounds that elicit an immune checkpoint blockade (ICB) have shown tangible results during a short period
Many studies have demonstrated that PD-1/PD-L1 targeted therapy provides a promising cancer immunotherapy approach through the inhibition of multiple stages of the immune response between
PD-L1 can be upregulated in accordance with infiltrating immune cells and the changing microenvironment within tumors, suggesting that it may prove to be a biomarker of cancer immunotherapy [1,4]

Summary

Introduction

Studies of potential anticancer compounds that elicit an immune checkpoint blockade (ICB) have shown tangible results during a short period. The recent research and development of immune checkpoint inhibitors, including monoclonal antibodies (mAbs) and small molecules for ICB-based immunotherapy, represents a major advance toward controlling a growing number of malignancies using immunosuppressive mechanisms for cancer treatment [1,2]. PD-1 is expressed in various immune-related cells, including T-cells, B-cells, and natural killer cells. PD-1 negatively regulates T-cell activity at the immune response stage by interacting with PD-L1 and PD-L2 through phosphatase activity. Through these interactions, PD-1 inhibits the kinase signaling of the associated ligand pathways, which serves to suppress T-cell activation

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